IL-15 is a cytokine crucial for both the generation and the maintenance of memory CD8 T cells. However, the functions of IL-15 are mediated via a novel mechanism called trans-presentation, which is not yet clearly understood. Trans-presentation is a mechanism of cytokine delivery by a specific cell type that expresses IL- 15 on the cell surface via a high affinity IL-15Ra and presents it to an opposing cell, thus inducing an IL-15 response. As yet, little is known about the cell types mediating this function or the parameters controlling this specific cell-cell interaction. The overall objective of this proposal is to better understand the mechanism that regulates the homeostatic proliferation of memory CD8 T cells. The central hypothesis is that dendritic cells (DCs) regulate the differentiation and homeostasis of memory CD8 T cells via IL-15 trans-presentation. This hypothesis is drawn on previous data demonstrating that expression of IL-15Ra, which mediates trans- presentation of IL-15, is required by hematopoietic cells but not by memory CD8 T cells themselves. The specific aims of this proposal are: Aim 1: Examine the contribution of DC-mediated IL-15 trans-presentation in the maintenance of memory CD8 T cells. Specifically, whether DCs expression of IL-15Ra is sufficient for memory CD8 T cell homeostasis will be tested. In addition, whether alterations in DC numbers affect CD8 T cell homeostatic proliferation and the existence of DCs interactions with memory CD8 T cells will be assessed. Aim 2: Determine the extent to which specific DC subsets differentially mediate memory CD8 T cell homeostasis. As DCs are heterogeneous, it will be determined if memory CD8 T cell homeostasis is mediated by a specific DC subset. Aim 3: Identify if differences in the homeostasis of memory CD8 T cell subsets are due to differential requirements for IL-15 trans-presentation by DCs. Two major subsets of memory CD8 T cells have been identified that differentially respond to homeostatic signals in vivo. It will be determined if this is due to differential responses to DC-mediated IL-15 trans-presentation. The rationale for this study is so future investigations can identify the necessary cellular features and potential regulators of IL-15 trans-presentation. The scientific progress in understanding the field of CD8 memory T cell homeostasis is crucial for designing vaccines, maintaining immunity to infections, and enhancing immunotherapy using adoptive therapies of CD8 T cells.